This R01 renewal proposes multimodality magnetic resonance imaging (MRI) study of differences in age-related patterns of frontotemporal (FT) connectivity in adolescents and adults with and without bipolar disorder (BD) and the genetic factors that influence them. Despite severe consequences of BD in suffering for individuals, their families and communities, and the high associated rate of suicide, the biological mechanisms that underlie the development of BD and its effective treatment remain unclear. Currently, there is no biological marker to diagnose BD or to guide who might benefit from a specific treatment, though incorrect treatment can adversely affect prognosis and many with BD suffer from refractory symptoms. It is critical to understand how specific genetic predispositions lead to specific brain differences to improve detection, target treatments to those most likely to benefit based on their biology and discover new mechanisms to target for novel treatment development. Major challenges for the field also include presentations of BD that differ over the lifespan for reasons not understood, limiting ability to adapt detection and treatments for life phases. Progress of our research program includes identification of a FT neural system that subserves emotional processing as central in BD. Importantly, this system changes over the lifespan. Our current work supports progressive differences in FT gray matter between those with BD and healthy comparison (HC) individuals that emerge as significantly divergent in late adolescence/early adulthood and implicates neurotrophic genes (e.g. brain-derived neurotrophic factor, BDNF) in the neurodevelopmental differences. The white matter (WM) providing the connections within this FT neural system is increasingly implicated in BD. In progress towards our new aims, with a new focus on WM, preliminary diffusion tensor imaging (DTI) analyses suggest patterns of WM development in healthy individuals are characterized by increases in structural integrity of FT WM through the 4th decade of life, followed by decreases. Our preliminary data also support a divergent pattern for WM in adolescents and adults with BD that results in decreases in the structural integrity of WM in BD, with a peak in the decreases compared to HC individuals in the early 4th decade. This raises the important possibility of windows to prevent developmental progression of WM abnormalities in BD into adulthood. Moreover, the data implicate a gene associated with WM development, neuregulin 1 (NRG1), in influencing FT WM integrity in BD. In this renewal we therefore plan to extend our study of the FT neural system in BD using multimodality MRI to study WM with DTI, and associated FT functional connectivity with functional MRI methods, in a larger sample (including 150 new adolescents and adults with BD and 150 HCs) that will permit modeling of differences in age-related patterns and effects of NRG1 and other implicated genes. This program is devoted to a long-term goal of enhancing ability to treat individuals with BD more specifically, based on their genetic background and point in their lifespan, and development of more effective detection, treatment and prevention strategies.